Systems that deliver certain drugs to a patient (e.g., distributed preferentially to a particular tissue or cell type or to a specific diseased tissue more than to normal tissue) or that control release of drugs have long been recognized as beneficial.
For example, therapeutics that include an active agent distributed preferentially to a specific diseased tissue more than to normal tissue, may increase the exposure of the drug in those tissues over others in the body. This is particularly important when treating a condition such as cancer where it is desirable that a cytotoxic dose of the drug is delivered to cancer cells without killing the surrounding non-cancerous tissue. Effective drug distribution may reduce the undesirable and sometimes life threatening side effects common in anticancer therapy.
Nanoparticles, by virtue of their size and surface properties, should allow prolonged circulation in the vasculature and preferential tissue accumulation through defective architecture of diseased tissues/tumours via the Enhanced Permeation and Retention effect.
Therapeutics that offer controlled release therapy also must be able to deliver an effective amount of drug, which is a known limitation in some nanoparticle delivery systems. For example, it can be a challenge to prepare nanoparticle systems that have an appropriate amount of drug associated with each nanoparticle, while keeping the size of the nanoparticles small enough to have advantageous delivery properties.
Accordingly, a need exists for nanoparticle therapeutics and methods of making such nanoparticles that are capable of delivering therapeutic levels of the therapeutic agent to treat diseases such as cancer, while also reducing patient side effects.
Cancer (and other hyperproliferative disease) is characterised by uncontrolled cellular proliferation. This loss of the normal regulation of cell proliferation often appears to occur as the result of genetic damage to cellular pathways that control progress through the cell cycle.
In eukaryotes, an ordered cascade of protein phosphorylation is thought to control the cell cycle. Several families of protein kinases that play critical roles in this cascade have now been identified. The activity of many of these kinases is increased in human tumours when compared to normal tissue. This can occur by either increased levels of expression of the protein (as a result of gene amplification for example), or by changes in expression of co activators or inhibitory proteins.
Aurora Kinases (Aurora-A, Aurora-B and Aurora-C) encode cell cycle regulated serine-threonine protein kinases (summarised in Adams et al., 2001, Trends in Cell Biology. 11(2): 49-54). These show a peak of expression and kinase activity through G2 and mitosis and a role for human Aurora kinases in cancer has long been implicated.
The Aurora Kinase inhibitor known as AZD1152 (2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)amino)ethyl dihydrogen phosphate), pictured below, also known as barasertib, was first disclosed in International Patent Application WO2004/058781 (Example 39) and has been studied by AstraZeneca as a potential treatment for various cancers. However there are practical challenges in the clinical administration of AZD1152 as an intravenous solution delivered continuously over multiple days.

It is known that AZD1152 is metabolized in vivo to a compound known as AZD1152 hqpa (2-(3-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide), also disclosed in WO2004/058781. AZD1152 hqpa is in fact, to a large extent, the moiety exerting the biological effect when AZD1152 itself is administered. However pharmaceutical compositions of AZD1152 hqpa, particularly those suitable for commercial administration, have not previously been specifically described or tested.

Nanoparticulate formulations including basic therapeutic agents with a protonatable nitrogen are described in WO2014/043625.